Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]=1[O:16]C)([CH3:3])[CH3:2].B(Br)(Br)Br.O.C(OCC)C>C(Cl)Cl>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]=1[OH:16])([CH3:3])[CH3:2]
Reactant: COc1c(-c2ccccc2)cccc1C(C)C
Agent: BrB(Br)Br
Solvent: CCOCC
Solvent: O
Solvent: ClCCl
Product: CC(C)c1cccc(-c2ccccc2)c1O
Temperature: -78 °C
Yield: 94 %

Procedure:
1.98 g (8.64 mmol) of 2-bromo-6-isopropylanisol, 2.10 g (17.28 mmol) of phenylboronic acid, 96 mg (0.43 mmol) of palladium acetate, 0.225 g (0.86 mmol) of triphenylphosphine and 11 g (51.84 mmol) of potassium phosphate were placed in a flask, and a mixed solution of 8 ml of water and 32 ml of dimethoxyethane was added thereto. The mixture was refluxed at room temperature for 12 hours. After the refluxed solution was cooled to room temperature, 15 ml of an aqueous ammonium chloride solution and 30 ml of diethyl ether were added thereto. Then, the organic layer was separated and the residue was extracted with diethyl ether. The collected organic layer was dried over magnesium sulfate, and volatile materials were removed therefrom, thus obtaining 2 g of 2-isopropyl-6-phenylanisol as a gray solid. The obtained anisol was dissolved in 15 ml of methylene chloride without a separate purification process, and then 12 ml of boron tribromide (1M methylene chloride) was added dropwise thereto at −78° C., and the mixture was warmed slowly to room temperature and allowed to react for 12 hours. After completion of the reaction, a mixed solution of 15 ml of water and 30 ml of diethyl ether was added thereto. The organic layer was separated and the aqueous layer was extracted with diethyl ether (15 ml×3). The collected organic layer was dried, and volatile components were removed in a vacuum. The residue was purified using a silica gel chromatography column in a mixed solvent of hexane and methylene chloride, thus obtaining 1.72 g of 2-isopropyl-6-phenylphenol as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][CH:15]([C:17]([F:20])([F:19])[F:18])[N:14]3[N:21]=[C:22]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([C:30](O)=[O:31])[CH:25]=4)[CH:23]=[C:13]3[NH:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N:33]1([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][CH:15]([C:17]([F:20])([F:18])[F:19])[N:14]3[N:21]=[C:22]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([C:30]([N:36]5[CH2:35][CH2:34][N:33]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:38][CH2:37]5)=[O:31])[CH:25]=4)[CH:23]=[C:13]3[NH:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1ccc(C2CC(C(F)(F)F)n3nc(-c4ccnc(C(=O)O)c4)cc3N2)cc1OC
Product: COc1ccc(C2CC(C(F)(F)F)n3nc(-c4ccnc(C(=O)N5CCN(C(=O)OC(C)(C)C)CC5)c4)cc3N2)cc1OC
Yield: 42.9 %

Procedure:
Example ER-897034 was prepared in two steps from 4-(5-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-2-yl)picolinic acid (25 mg, 0.056 mmol) and commercially available tert-butyl piperazine-1-carboxylate (31 mg, 0.167 mmol) in a manner similar to that of example D-6 to afford intermediate tert-butyl 4-(4-(5-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-2-yl)picolinoyl)piperazine-1-carboxylate (15 mg, 0.024 mmol, 44% yield). Then, this intermediate (13 mg, 0.021 mmol) was treated with HCl in a manner similar to that of example ER-897560 to afford the desired product ER-897034 (12.2 mg, 98% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH:12]=[CH:11][C:10]=2[C:18]([OH:20])=O)=[C:4]([F:21])[CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:44][O:45][CH2:46][C@@H:47]([OH:49])[CH3:48].CCN(C(C)C)C(C)C>O1CCOCC1.C(OCC)(=O)C>[OH:49][C@@H:47]([CH3:48])[CH2:46][O:45][NH:44][C:18]([C:10]1[CH:11]=[CH:12][C:13]2[N:14]([CH:15]=[N:16][CH:17]=2)[C:9]=1[NH:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:21])=[O:20]
Reactant: O=C(O)c1ccc2cncn2c1Nc1ccc(Br)cc1F
Reactant: C[C@H](O)CON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](O)CONC(=O)c1ccc2cncn2c1Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.5 %

Procedure:
To a solution of 5-(4-bromo-2-fluoro-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid (271 mg, 0.77 mmol) in dioxane (3.9 mL) was added HOBT (306 mg, 2.3 mmol) and EDCI (442 mg, 2.3 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes then (S)-1-aminooxy-propan-2-ol hydrochloride (294 mg, 2.3 mmol) and DIPEA (1.2 mL, 6.9 mmol) were added, the mixture was then stirred for 60 hours at ambient temperature. The reaction mixture was diluted with ethyl acetate then washed with a saturated aqueous solution of sodium bicarbonate followed by water and brine. The organic phase was isolated, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0 to 100%, ethyl acetate in dichloromethane, then gradient 0 to 10%, methanol in dichloromethane) to afford the title compound as a green/yellow solid (80 mg, 25%). LCMS (method A): RT=5.71 min, [M+H]+=423/425. 1H NMR (DMSO-d6): 8.10 (1H, s), 7.51 (1H, dd, J=10.87, 2.22 Hz), 7.43 (1H, s), 7.39 (1H, d, J=9.31 Hz), 7.18-7.14 (1H, m), 6.88 (1H, d, J=9.31 Hz), 6.51 (1H, t, J=8.85 Hz), 4.69 (1H, s), 3.68-3.59 (1H, m), 3.42 (2H, d, J=5.81 Hz), 0.95 (3H, d, J=6.35 Hz).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12].[H-].[Na+].Cl[C:16]1[N:17]=[C:18]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:20][CH:21]=1>O1CCCC1>[C:28]1([C:18]2[N:17]=[CH:16][C:21]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)=[N:20][C:19]=2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: OCCCCOC1CCCCO1
Reactant: Clc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(-c2ncc(OCCCCOC3CCCCO3)nc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.8 %

Procedure:
1.57 g of 4-(2-tetrahydropyranyloxy)-1-butanol was dissolved in 20 ml of tetrahydrofuran and 360 mg of 60% sodium hydride was added under ice cooling, followed by stirring at room temperature for 1.5 hours. The mixture was refluxed for 30 minutes and ice-cooled again and 2.00 g of 5-chloro-2,3-diphenylpyrazine was added. After stirring for 40 minutes, the mixture was heated to 80° C., stirred at the same temperature for 4.5 hours and then stirred at room temperature for 88 hours. The reaction solution was combined with ice water, extracted with ethyl acetate and then washed with saturated brine. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to obtain 2.39 g of the desired compound as an oily substance.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH:3]([C:14]([OH:16])=[O:15])[NH:2]1.[CH:17]1(NC2CCCCC2)[CH2:22]CCC[CH2:18]1.C(O)C.C(I)CC.[C:37](=[S:39])=[S:38]>>[CH:11]1([NH:12][CH:13]2[CH2:5][CH2:4][CH2:3][CH2:14][CH2:1]2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[CH2:18]([S:39][C:37]([N:2]1[CH:3]([C:14]([OH:16])=[O:15])[CH2:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:12][C:13]=2[CH2:1]1)=[S:38])[CH2:17][CH3:22]
Reactant: O=C(O)C1Cc2c([nH]c3ccccc23)CN1
Reactant: S=C=S
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: CCO
Solvent: CCCI
Product: CCCSC(=S)N1Cc2[nH]c3ccccc3c2CC1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of (3RS)-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (4.32 g), dicyclohexylamine (7.3 g) and 50% ethanol (55 ml) is added dropwise carbon disulfide (1.2 ml). The mixture is stirred at room temperature for 30 minutes, and thereto is added dropwise n-propyl iodide (3.4 g). The mixture is further stirred at room temperature for 10 minutes. The reaction mixture is distilled to remove the solvent. The resulting precipitates are collected by filtration and washed with ether to give dicyclohexylamine salt of the title compound. This product is treated with 10% HCl to give the title compound (4.6 g, 69%) as colorless needles, m.p. 180° C. (decomp.) (recrystallized from ethanol).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].C[Si]([CH2:9][N:10]=[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[SH-]C)(C)C>C1COCC1>[C:14]1([C:11]2[CH2:3][CH:2]([C:1]#[N:4])[CH2:9][N:10]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C=CC#N
Reactant: C[SH-]C(=NC[Si](C)(C)C)c1ccccc1
Solvent: C1CCOC1
Product: N#CC1CN=C(c2ccccc2)C1
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
A solution of acrylonitrile (0.65 mL; 0.01 mol) and N-(trimethylsilyl)methyl-S-methyl-benzenethioimidate (2.4 g; 0.01 mol) in THF (100 mL) is cooled to -5° C. in an ice-acetone bath. Under a nitrogen purge, a solution of tetrabutylammonium fluoride (1.0 mL of a 1N solution in THF) and THF (20 mL) is added dropwise over 30 minutes The solution is stirred another 30 minutes at -5° C. , and then allowed to warm slowly to ambient. Stirring is continued another 18 hours, and then solvent is removed under reduced pressure. The residue is partitioned between ether/water and the water layer extracted with fresh ether. The combined organic layer is washed with water, then saturated sodium chloride. The solution is dried over MgSO4, and cooling the filtrate causes precipitation of an off-white solid (1.2 g; 70% theoretical yield) whose spectral characteristics are identical to the material described by Tsuge [J. Org. Chem. 52, 2523 (1987)].
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[CH2:21][N:22]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:23][CH3:24])[CH:10]=1.O.[OH-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO>[CH2:28]([O:27][C:25]([N:22]([CH2:21][C:12]1[CH:13]=[C:14]([C:17]([F:18])([F:19])[F:20])[CH:15]=[CH:16][C:11]=1[C:9]1[CH:10]=[C:5]([CH2:4][C:3]([OH:35])=[O:2])[CH:6]=[N:7][CH:8]=1)[CH2:23][CH3:24])=[O:26])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1-c1cncc(CC(=O)OC)c1)C(=O)OCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cncc(CC(=O)O)c1)C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
(5-{2-[(N-Benzyloxycarbonyl-N-ethyl-amino)-methyl]-4-trifluoromethyl-phenyl}-pyridin-3-yl)-acetic acid methyl ester (0.1 g, 0.2 mmol) in THF (2 mL), MeOH (0.5 mL), and H2O (0.5 mL) was treated with lithium hydroxide (0.03 g) and stirred at room temperature until no starting material was seen by analytical LCMS. The reaction was neutralized with citric acid to pH 4 and extracted with EtOAc, and the combined organic layers were washed with H2O, dried over MgSO4, filtered, and concentrated to give Compound 12.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][N:17]([N:20]=[CH2:21])[CH2:16][CH2:15]3)=[O:13])[C:6]=2[CH:22]=1.[BH4-].[Na+].O1CCCC1>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:15][CH2:16][N:17]([NH:20][CH3:21])[CH2:18][CH2:19]3)=[O:13])[C:6]=2[CH:22]=1
Reactant: C=NN1CCN(C(=O)Cn2c(=O)sc3ccc(Cl)cc32)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CNN1CCN(C(=O)Cn2c(=O)sc3ccc(Cl)cc32)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 17.6 %

Procedure:
A mixture of 5-chloro-3-[(4-methyleneamino-1-piperazinyl)carbonylmethyl]-2-benzothiazolinone (5.09 g), sodium borohydride (284 mg), tetrahydrofuran (80 ml), and ethanol (70 ml) was stirred for 3 hours at room temperature. The reaction mixture was concentrated under reduced pressure and the residue obtained was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (20:1). The fractions containing the desired compoundwere combined and concentrated under reduced pressure. The white residue was dissolved in chloroform (5 ml), and 20% solution of hydrogen chloride in ethanol (1 ml) was added to the above solution. The white precipitates were filtered and recrystallized from a mixture of ethanol (10 ml) and water (2 ml) to give colorless crystals of 5-chloro-3-[(4-methylamino-1-piperazinyl)carbonylmethyl]-2-benzothiazolinone hydrochloride (0.5 g).
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:9]1([C:3]2[N:4]=[C:5]([NH2:8])[N:6]=[N:7][C:2]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1ccccc1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Product: Nc1nnc(-c2ccccc2)c(-c2ccccc2)n1
Yield: 43.3 %

Procedure:
5,6-Diphenyl-1,2,4-triazin-3-amine (86.0 mg, 42%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.21 g, 0.8 mmol) and phenyl boronic acid (0.11 g, 0.92 mmol) according to the general procedure of Example 1.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]3[N-:40][C:39]([C:4]2=[CH:3][CH:2]=1)=[N:38][C:36]1=[N:37][C:29]([C:30]2[C:35]1=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:28][C:26]1=[N:27][C:19]([C:20]2[C:25]1=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:18][C:16]1[N-:17][C:9](=[C:10]2[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]2)[N:8]=3.[O-2].[Ti+4:42]>S(=O)(=O)(O)O>[Ti:42].[CH:12]1[CH:13]=[CH:14][C:15]2[C:10](=[C:9]3[N:8]=[C:7]4[N:40]=[C:39]([C:4]5[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=54)[N:38]=[C:36]4[NH:37][C:29]([C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=54)=[N:28][C:26]4=[N:27][C:19]([C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=54)=[N:18][C:16]=2[NH:17]3)[CH:11]=1
Reactant: [Ti+4]
Reactant: c1ccc2c(c1)-c1nc3nc(nc4[n-]c(nc5[n-]c(nc-2n1)c1ccccc51)c1ccccc41)-c1ccccc1-3
Agent: O=S(=O)(O)O
Agent: [O-2]
Product: [Ti]
Product: c1ccc2c(c1)-c1nc-2nc2[nH]c(nc3nc(nc4[nH]c(n1)c1ccccc41)-c1ccccc1-3)c1ccccc21
Temperature: 5 °C
Reaction time: 1 h

Procedure:
Ten parts of the TiOPc crude prepared in Example 1 was gradually dissolved in 40 parts of 97% sulfuric acid at 2° C., and their mixture was stirred for 1 hour with maintaining its temperature at not higher than 5° C. Then, the resulting sulfuric acid solution was slowly poured into 400 parts of ice water with stirring at a high speed, and crystals precipitated were filtrated. The crystals were washed with distilled water until the acid did not remain, and then dried to give 9 parts of a titanium phthalocyanine compound. One part of this TiOPc was milled by a ball mill for 80 hours.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]([NH2:12])=[CH:5][CH:4]=1.Cl.Cl[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:12][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9]
Reactant: Clc1ccncc1
Reactant: COc1ccc(N)c(C(=O)O)c1
Agent: Cl
Product: COc1ccc(Nc2ccncc2)c(C(=O)O)c1
Yield: 111.7 %

Procedure:
5-Methoxy-2-(4-pyridinylamino)benzoic acid was prepared from 4.9 g of 5-methoxyanthranilic acid and 4.4 g of 4-chloropyridine hydrochloride according to the procedure of Example 1, part (a). There was obtained 8.0 g of 5-methoxy-2-(4-pyridinylamino)benzoic acid which was recrystallized from water and used directly in the next reaction.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:22][C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=2[Cl:32])[C:26]([OH:28])=O)=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:13]=2)=[N:6][CH:7]=1.[N:33]1([CH2:38][CH2:39][NH2:40])[CH2:37][CH2:36][CH2:35][CH2:34]1.C(N(CC)C(C)C)(C)C>C1COCC1>[ClH:32].[ClH:32].[Br:1][C:2]1[C:3]([O:22][C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=2[Cl:32])[C:26]([NH:40][CH2:39][CH2:38][N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)=[O:28])=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:13]=2)=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(Cl)c(Oc2cc(Nc3nc(CCc4ccccc4)cs3)ncc2Br)c1
Reactant: NCCN1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cl
Product: O=C(NCCN1CCCC1)c1ccc(Cl)c(Oc2cc(Nc3nc(CCc4ccccc4)cs3)ncc2Br)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 159.3 %

Procedure:
A vial was charged with 3-(5-bromo-2-(4-phenethylthiazol-2-ylamino)pyridin-4-yloxy)-4-chlorobenzoic acid (0.050 g, 0.0942 mmol), 1-pyrrolidine ethanamine (0.013 g, 0.113 mmol), N,N-diisopropylethylamine (0.0328 mL, 0.188 mmol), and THF (3 mL). Diethyl cyanophosphononate (0.0239 g, 0.132 mmol) was added and the reaction was stirred for 4 hours at ambient temperature. The reaction mixture was concentrated and the residue was partitioned between water and ethyl acetate. The organic later was dried and concentrated, and the crude material was purified by preparative TLC using 5% ammoniated methanol in DCM. The isolated material was treated with 2M HCl in ether and the isolated solids were dried in vacuum to give the title compound (0.035 g, 51.5% yield) as a light yellow solid. 1H NMR (CDCl3) δ 8.99 (s, 1H), 8.36 (s, 1H), 7.96 (m, 2H), 7.57 (m, 1H), 7.25 (m, 1H), 7.15 (m, 3H), 6.70 (s, 1H), 6.30 (s, 1H), 3.85 (m, 4H), 3.35 (m, 2H), 2.93 (m, 6H), 2.14 (m, 4H).
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([C:14]1[C:15]([F:35])=[C:16]([N:22](S(CCC)(=O)=O)[S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24])[CH:17]=[C:18]([F:21])[C:19]=1[F:20])=[O:13])=[CH:7][CH:6]=2.[CH3:36][C:37]1[NH:38][CH:39]=[CH:40][N:41]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:35][C:15]1[C:14]([C:12]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]=[CH:3][C:2]([N:38]2[CH:39]=[CH:40][N:41]=[C:37]2[CH3:36])=[N:11]3)=[O:13])=[C:19]([F:20])[C:18]([F:21])=[CH:17][C:16]=1[NH:22][S:23]([CH2:26][CH2:27][CH3:28])(=[O:24])=[O:25]
Reactant: Cc1ncc[nH]1
Reactant: CCCS(=O)(=O)N(c1cc(F)c(F)c(C(=O)c2ccc3ncc(Cl)nc3c2)c1F)S(=O)(=O)CCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1cc(F)c(F)c(C(=O)c2ccc3ncc(-n4ccnc4C)nc3c2)c1F
Temperature: 90 °C
Reaction time: 4 h
Yield: 0.7 %

Procedure:
To a solution of N-(3-(3-chloroquinoxaline-6-carbonyl)-2,4,5-trifluorophenyl)-N-(propylsulfonyl)propane-1-sulfonamide (50 mg, 9.6 mmol, 1.0 eq.) in DMF (2 mL) was added 2-methyl-1H-imidazole (18 mg, 24 mmol, 2.5 eq.) and Cs2CO3 (59 mg, 19.2 mmol, 2.0 eq.). The resulting mixture was stirred at 90° C. for 4 h, then washed with water and extracted with EA (20 mL×3). The combined organic phase was dried over Na2SO4, filtered and concentrated. The resulting residue was purified by flash column chromatography (DCM/MeOH-30/1, v/v) to afford N-(2,4,5-trifluoro-3-(3-(2-methyl-1H-imidazol-1-yl)quinoxaline-6-carbonyl)phenyl)propane- 1-sulfonamide (34 mg, 73%). LRMS (M+H+) m/z calculated 490.1, found 489.9. 1H NMR (DMSO, 400 MHz) δ 10.13 (brs, 1 H), 9.46 (s, 1 H), 8.56 (s, 1 H), 7.95 (s, 1 H), 8.36 (brs, 2 H), 7.77 (m, 1 H), 7.94 (s, 1 H), 2.69 (s, 3 H), 3.21 (m, 2 H), 1.75 (m, 2 H), 0.97 (s, 3 H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[S:42]1[C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=2[CH:44]=[C:43]1[S:51](Cl)(=[O:53])=[O:52]>C(#N)C>[S:42]1[C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=2[CH:44]=[C:43]1[S:51]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:53])=[O:52]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: O=S(=O)(Cl)c1cc2ccccc2s1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3cc4ccccc4s3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 28.1 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0300 g, 0.0650 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 1-benzothiophene-2-sulfonylchloride (0.0357 g, 0.195 mmol) to obtain 4-(benzothiophene-2-sulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0120 g, yield 33%).
Reaction SMILES: O(P(O[C:18]1[N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=1)(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[O:31]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1B(O)O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[O:31]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:43]=1[C:18]1[N:19]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCOC=C1OP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: OB(O)c1ccccc1Oc1ccccc1
Product: CC(C)(C)OC(=O)N1CCOC=C1c1ccccc1Oc1ccccc1
Yield: 25 %

Procedure:
This compound was prepared from tert-butyl 5-((diphenoxyphosphoryl)oxy)-2H-1,4-oxazine-4(3H)-carboxylate and 2-phenoxyphenylboronic acid using a procedure similar to that described in Example 2 (Steps 1-3a) above. The product was isolated as a white solid (25% yield); 1H-NMR (d6-DMSO) 1.07 (9H, s), 3.09 (2H, m), 3.97 (2H, m), 6.19 (1H, s), 6.78 (2H, m), 6.97-7.04 (2H, m), 7.15-7.19 (1H, m), 7.26-7.32 (4H, m); MS ES(+) 298.0 (M+-tBu). IR λmax=1692 cm−1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:12][CH:13]([CH3:15])[CH3:14])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH2:23][CH2:24]O)[CH:17]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1COCC1.CCCCCC>[CH:13]([O:12][C:4]1[CH:5]=[C:6]([CH:11]=[C:2]([O:1][CH2:24][CH2:23][CH2:22][C:18]2[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=2)[CH:3]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:15])[CH3:14]
Reactant: OCCCc1cccnc1
Reactant: COC(=O)c1cc(O)cc(OC(C)C)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)c1cc(OCCCc2cccnc2)cc(OC(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
To a solution (60 ml) of methyl 5-hydroxy-3-isopropoxybenzoate (2.0 g) and 3-(pyridin-3-yl)propanol (1.6 g) in THF were added successively 1,1′-(azodicarbonyl)dipiperidine (2.9 g) and tributylphosphine (2.8 ml) under ice-cooling, and the mixture was stirred overnight at room temperature. n-Hexane (100 ml) was added to the reaction mixture, and the precipitated crystals were removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (LL, Biotage cartridge, ethyl acetate:n-hexane=15:85→1:4) to give methyl 3-isopropoxy-5-(3-pyridin-3-ylpropoxy)benzoate (2.70 g, 86%) as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[S:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1C=CC=CC=1>[CH2:1]([NH:8][C:9]([NH:18][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[S:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: NCc1ccccc1
Reactant: CCCCCCCN=C=S
Solvent: c1ccccc1
Product: CCCCCCCNC(=S)NCc1ccccc1
Yield: 105.9 %

Procedure:
To a solution of 3.1 grams (0.02 mole) of n-heptyl isothiocyanate dissolved in 25 milliliters of benzene, was added 2.1 grams (0.02 mole) benzylamine. The resulting exothermic reaction resulted in a temperature rise from 24° C. to 35° C. The mixture was then refluxed for 20 minutes on the steam-bath until the mixture reaced neutral pH and the mixture was evaporated under vacuum to yield 5.6 grams of n-heptyl-3-benzyl thiourea, ND30 =1.5513.